Environmental Influence in Autoimmune Diseases. Mark Gourley, MD

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1 Environmental Influence in Autoimmune Diseases Mark Gourley, MD

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4 Newsweek January, 2003

5 Current Knowledge of Environment and Myositis Environment Genes Autoimmunity

6 What Is an Environmental Exposure? Defined - susceptibility factors for an illness that are not inherited Two types: Macroenvironment (uncontrolled) Atmospheric pollution Water contamination Microenvironment (controlled) Workplace Diet Leisure time

7 Immune-mediated Disease (IMD) Autoimmunity Hundreds of acquired disorders in which the immune system likely play a pathogenic role Third most common group of diseases in the U.S. - After cardiac disease and cancer - and are becoming more common High rate of chronic illness and death resulting in great costs to society Pathogeneses are poorly understood but likely involve chronic immune activation after environmental exposures in genetically susceptible individuals

8 Types of Immune-mediated Disease Hypersensitivity and allergic disorders (allergic rhinitis, sinusitis, asthma) Adverse reactions to drugs, biologics, medical devices, foods (drug-induced lupus, vasculitis) Immune suppression and decreased ability to resist disease (polychlorinated biphenyls & respiratory infections) Organ-specific autoimmune diseases (Hashimoto s thyroiditis, type 1 diabetes) Systemic autoimmune diseases (myositis, rheumatoid arthritis, lupus, systemic sclerosis)

9 Possible Environmental Triggers of Immune-mediated Diseases Infectious agents Bacteria / parasites: Streptococci, Borrelia, others Viruses: +RNA, DNA, retroviruses, others Non-infectious agents Foods: L-tryptophan, adulterated rapeseed oil Drugs: D-penicillamine, hydralazine, many others Biologics: Vaccines, cytokines Medical devices: Collagen and silicone implants Occupational exposures: Silica, beryllium, vinyl chloride Other exposures: UV light, mercury, petrochemicals

10 Examples - Caprine Arthritis Encephalitis Caused by a virus

11 Erythema Infectiosum (Fifth Disease) Caused by a virus

12 Infectious Disease and Autoimmunity Some infections are decreasing while autoimmune disease is increasing.

13 Certain strains of mice develop diabetes when raised in specific germ free environments Bacteria and viruses can be helpful for the immune system

14 Xenobiotics Chemicals found in the environment, drugs or in food that are not produced by the human body. Xenobiotics are capable of influencing the immune system. The number or xenobiotics that are capable of causing autoantibody formation is growing.

15 Animal Models of Autoimmunity Triggered by Xenobiotics Xenobiotic Animal Strain Autoimmunity Human counterpart Mercury Rats Ab disease Lupus Gold Rats IC-kidney disease Kidney inflammation Penicillamine Mice Ab to a receptor Myasthenia Gravis Procainamide Mice ANA, lung disease Lupus

16 Chemicals Associated With Autoimmunity SLE Allopurinol, Carbamazepine, Cocaine, Dapsone, Gold, Hydralazine, INH, Penicillamine, Procainamide, Sulfonamides Scleroderma Bleomycin, Silicon, Trilene, Vinyl chloride Cytopenias Methyldopa, Gold, Penicillamine, Penicillin Renal disease Cadmium, Gold, Mercury No good associations for myositis

17 Mechanisms Leading to Impaired Immunologic Tolerance Abnormal cytokine secretion Modified self antigen Abnormal MHC molecule expression Failure to delete autoreactive lymphocytes Lack of tolerance to autoreactive lymphs Abnormal adhesion molecule expression Antigen mimicry Many different ways disease may occur

18 Genes are very important

19 Evidence for the Environment s Influence Less than 50% of identical twins get the disease Strong timing connection with some environmental exposures and disease onset Dechallenge = disease improvement after agent removal Rechallenge = disease recurrence after re-exposure Evidence from animal models Epidemiology studies between exposures and diseases

20 Myositis Group of syndromes whose hallmarks are chronic muscle weakness from muscle inflammation of unknown cause About 0.01% of US population affected; more common in women, frequent onset age 30s and 40s Dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM) are the most common clinical forms Common problems include: muscle weakness, swelling of the hands and feet, pain and stiffness of the joints; rashes; GI (reflux, dysphagia and constipation); lung (ILD, fibrosis) involvement; Non-specific symptoms such as extreme fatigue, generalized weakness, weight loss, and vague aching of muscles, joints and bones

21 Global UV Light Levels Predict the Proportion of DM Around the World 100 Guatemala % Dermatomyositis R = 0.939, P < Mexico city Guadalajara New Delhi Santiago Tokyo Seoul Bethesda Barcelona Warsaw Aachen Nijmgen 0 Stockholm Glasgow UV Exposure (Joules/ m 2 )

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23 Very Few Studies have looked at Myositis

24 Other Environmental Items Remember the sun Ultraviolet rays Too much in excess Stress, Drugs (recreational, anabolic steroids), Diet, Traumatic events Too little in excess Sleep, take care of your body, diet Eat right, sleep right, exercise, moderation

25 What Can We Do To Limit Exposure? Eat right, sleep right, stress to a minimum, take care of our bodies Take you medications Photoprotection it really works!

26 Possible Genotype-Ecotype- Phenotype Associations

27 Twin Sibling Study Study of the environment s influence on rheumatic disease RA, SLE, Scleroderma, Myositis Children and Adults Study Genetics, microchimerism, microarray Environmental exposures Follow 5 years Contact Adam Schiffenbauer or Fred Miller at the NIH in Bethesda, MD